Disruption of the mitochondrial hydrogen sulfide oxidation pathway is identified as a new pathomechanism associated with primary CoQ deficiency. These findings may help explain the clinical heterogeneity of this syndrome.

Synopsis

Disruption of the mitochondrial hydrogen sulfide oxidation pathway is identified as a new pathomechanism associated with primary CoQ deficiency. These findings may help explain the clinical heterogeneity of this syndrome.

For the first time, disruption of mitochondrial sulfide metabolism is found to be associated with primary CoQ deficiency.

Sulfide:quinone oxidoreductase (SQR) deficiency was related to residual CoQ levels and, as a consequence, thiosulfate sulfurtransferase (TST) activity was increased and the levels of thiols were modified.

Due to the accumulation of hydrogen sulfide, the levels of certain neurotransmitters in the cerebrum of Coq9R239X mice were altered and the blood pressure was reduced.

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Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo.

Synopsis

Coenzyme Q (CoQ) is an electron acceptor for sulfide‐quinone reductase (SQR), the first enzyme of the hydrogen sulfide oxidation pathway. Lack of CoQ is here shown to cause impairment of hydrogen sulfide oxidation in vitro and in vivo.

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SHOX mutations lead to SHOX deficiency, a disorder mostly characterized by isolated short stature and skeletal dysplasia. Co‐occurrence of CYP26C1 and SHOX mutations in patients and CYP26C1 loss in zebrafish experiments support a role for CYP26C1 variants in SHOX genotype modulation.

Synopsis

SHOX mutations lead to SHOX deficiency, a disorder mostly characterized by isolated short stature and skeletal dysplasia. Co‐occurrence of CYP26C1 and SHOX mutations in patients and CYP26C1 loss in zebrafish experiments support a role for CYP26C1 variants in SHOX genotype modulation.

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Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).

Synopsis

Mitochondria‐associated membranes (MAM) are contact sites between endoplasmic reticulum and mitochondria, and play a key role in cellular homeostasis. Here, disruption of the MAM is shown to be tightly involved in the pathology of amyotrophic lateral sclerosis (ALS).

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The sudden unexpected death of a child is a devastating event. One of the first questions a family will ask is “Why did this happen?” In some cases, the answer may become obvious during a postmortem examination, but in up to 40% of cases, the postmortem is negative (Bagnall et al, 2016). In the last 1–2 decades, an improved understanding of the genetic basis of the primary arrhythmia syndromes, the major cause of sudden unexplained death in children with structurally normal hearts, has greatly enhanced our ability to make a postmortem diagnosis (Van Norstrand & Ackerman, 2010). Establishing an accurate genetic diagnosis can not only answer the parents' question as to why did this happen to my child, but is invaluable for cascade screening of all family members to identify other individuals harbouring the same mutation and who therefore may be at risk of sudden cardiac death. However, even after screening for all of the established genes associated with primary arrhythmia syndromes, up to two thirds of unexplained cardiac deaths will remain unsolved. Such was the case for a family of Sudanese origin with a highly malignant form of exercise‐induced arrhythmias, originally reported by Bhuiyan et al (2007).

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Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.

Synopsis

Mutations in the novel TECRL gene were identified in patients with malignant exercise‐induced arrhythmias. Increased triggered electrical activity upon stimulation in patient‐specific hiPSC‐CMs was rescued by the antiarrhythmic drug flecainide.

Trans‐2,3‐enoyl‐CoA reductase‐like (TECRL) is preferentially expressed in the heart.

Mutations in TECRL cause lethal arrhythmias in humans.

Cardiac defects in TECRL patients are characterized by overlapping features of long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).

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The field of mitochondrial medicine is rapidly transitioning from preclinical observation to clinical application. Translation of promising data obtained in mouse models is not always straight‐forward, however. Building on their own work showing that a ketogenic diet induces mitochondrial biogenesis and delays the onset of disease in the Deletor mouse, Ahola et al administered modified Atkins diet (mAD) to five patients with mitochondrial myopathy caused by mitochondrial DNA deletions (Ahola et al, 2016). Surprisingly, mAD did not induce mitochondrial biogenesis in patients, but rather triggered the progressive damage of muscle cells, particularly those with impaired respiratory chain activity (the ragged‐red fibres). The subsequent extensive characterisation of the metabolic and molecular profile changes observed in patients and healthy controls provides a significant advance towards understanding the feasibility of dietary modification as a treatment strategy for mitochondrial diseases.

Pitceathly and Viscomi comment on a new report by Anu Suomalainen's team showing that a ketogenic modified Atkins diet induces muscle damage, especially of ragged‐red fibres, in human mitochondrial myopathic patients.

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A novel clinical DIAPH1 mutation (c.3610C>T) is found in two unrelated families, resulting in a constitutively active DIA1. Patients and mice expressing the DIA1(R1204X) protein show progressive hearing loss beginning in the high‐frequency range and mimicking a novel DFNA1 subtype.

Synopsis

A novel clinical DIAPH1 mutation (c.3610C>T) is found in two unrelated families, resulting in a constitutively active DIA1. Patients and mice expressing the DIA1(R1204X) protein show progressive hearing loss beginning in the high‐frequency range and mimicking a novel DFNA1 subtype.

A novel DIAPH1 mutation results in early termination of DIA1 at the diaphanous autoregulatory domain (DAD), R1204X.

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A red‐shifted channelrhodopsin (ReaChR) was targeted to retinal ganglion cells using three models in parallel: mouse, macaque, and human. Safe orange illumination was able to trigger light responses in all three systems.

Synopsis

A red‐shifted channelrhodopsin (ReaChR) was targeted to retinal ganglion cells using three models in parallel: mouse, macaque, and human. Safe orange illumination was able to trigger light responses in all three systems.

The red‐shifted channelrhodopsin ReaChR restored light responses at the retinal, cortical, and behavioral levels in blind rd1 mice, using light intensities below the safety limit for the human retina.

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